As a result of the importance of asymmetric synthesis in synthetic organic, medicinal, agricultural, and natural products chemistry, and their related industries, the discovery of chiral ligand-metal complexes that are capable of catalyzing reactions with high enantioselectivity, and generating optically pure or enantiomerically enriched products has been an area of intense research (see, for example, R. Noyori, “Asymmetric Catalysis in Organic Synthesis”, Wiley, N.Y. 1994). Unfortunately, catalyst discovery and optimization has traditionally been conducted using the laborious and time consuming one-at-a-time technique, which involves the synthesis of “potential” catalysts one-at-a time and subsequently testing those “potential” catalysts one-at-a-time for activity.
In recent years, there has been a significant increase in the use of combinatorial chemistry techniques for the discovery of new catalysts (see, for example, Jandeleit et al. “Combinatorial Materials Science” Angew. Chem. Int. Ed. Engl. 1999, 38, 2494; Crabtree, R. H. “Speeding Catalyst Discovery and Optimization” Chemtech, April 1999, 21-26). One recent example of the use of combinatorial techniques for catalyst discovery and optimization is the discovery of a novel catalyst for alkene epoxidation (Francis, M. B., Jacobsen, E. N. Angew. Chem. Int. Ed. 1999, 38, 937) in which 192 different ligands were tested and visually selected for their metal-binding ability in a pooled assay with 30 different metal ion sources, and then screened for the ability to catalyze the epoxidation of trans-β-methylstyrene using gas chromatography. Other developments in catalyst discovery using combinatorial methods include the discovery of catalysts for metallocarbene C—H insertions (Burgess et al. Angew. Chem. Int. Ed. Engl. 1996, 35, 220), homochiral Lewis Acid catalysts for asymmetric aza-Diels-Alder reactions (Bromidge et al. Tetrahedron Lett. 1998, 39, 8905), and palladium-catalyzed allylic alkylations (Porte et al. J. Am. Chem. Soc. 1998, 120, 9810; Burgess et al. Tetrahedron. Asymmetry 1998, 9, 2465), to name a few. For a more comprehensive discussion of the use of combinatorial techniques in asymmetric catalysis, see Jandeleit et al., and references cited therein.
Although there has been a significant improvement in the discovery of new catalysts using combinatorial catalysis techniques, many of the techniques relied upon to assay these potential catalysts are still laborious and time consuming. For example, most of the assays rely on the use of traditional gas chromatography or mass spectrometry methods to analyze reaction products and typically can only analyze one sample every few minutes, and additionally require additional time between samples. One example of the progress towards the development of high-throughput screening techniques includes the use of mass tagged chiral acylating agents to diastereoselectively derivatize and automate qualtitive electrospray ionization mass spectrometry (ESI-MS) (Guo et al. Angew. Chem. Int. Ed. Engl. 1999, 38, 1755). This method, however, is still laborious and time consuming, particularly for the screening of as many as, or more than, 10,000 products, because each sample must be injected into the mass spectrometer (only samples with differing molecular weights may be combined) and requires approximately two minutes to complete. Therefore, the analysis of 10,000 reaction products, at two minutes per sample, including a 20 minute wash after every 36 samples, would require approximately 17.65 days (working 24 hours a day) to complete.
Clearly, there remains a need to develop truly high-throughput methods for the analysis of reaction products and/or mixtures, particularly for the determination of enantiomeric ratios, relative conversion and absolute configuration for large numbers (e.g., tens-of-thousands, or more) of reaction mixtures. A significant acceleration in the discovery and optimization of enantioselective catalysts, stoichiometric reagents, reactions, and reaction conditions would result if tens-of-thousands (or millions) of experiments, such as catalysis experiments, were able to be performed simultaneously in a relatively short amount of time, preferably within one working day, followed by high-throughput determination or identification of product characteristics including, but not limited to, functional group identity, percent yields, product enantiomeric ratios, relative conversions and absolute configurations.